From viral persistence to lipid imbalance: Immunological drivers of dyslipidemia in HIV

Dyslipidemia is a common comorbidity in people with human immunodeficiency virus (HIV) (PWH), driven by both viral persistence and antiretroviral therapy (ART), and it plays a pivotal role in cardiovascular disease (CVD) development through complex inflammatory and metabolic pathways. HIV infection is associated with dyslipidemia, with a reported prevalence of 53% among PWH, and dyslipidemia has been observed in both ART-naïve and ART-experienced individuals.[1] The typical lipid profile in untreated HIV infection features reduced levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), along with a progressive increase in triglyceride (TG) levels as the disease advances.[2] The advent of ART over the past three decades has transformed HIV into a manageable chronic condition; however, its long-term use introduces heterogeneous effects on lipid homeostasis. Among these, protease inhibitors (PIs) cause the most pronounced and enduring disruptions, and these disruptions often exceed the lipid disturbances attributable to HIV infection itself. Yet, in the evaluation of dyslipidemia profiles across different ART agents, most available evidence comes from switch therapy studies, where 48 weeks or 96 weeks serve as key time points. Analyses are conducted by comparing patients' lipid changes before and after switching from conventional ART regimens to newer-generation ones, and in such studies, integrase strand transfer inhibitors (INSTIs), whose "lipid-friendly" effects are widely recognized, are often designated as the reference group for assessing lipid changes (Table 1).[3–5] Notably, in treatment-naïve patients, clinical observations show that the use of INSTI may cause a slight increase in lipids within 48 weeks. However, this change is generally considered statistically insignificant and is mostly interpreted as a restorative manifestation of patients' metabolic function.[3] Table 1 - Effects of antiretroviral therapy agents on lipid profiles Class Agent TC TG LDL-C HDL-C PI Atazanavir/r ↑ ↑↑ ↑ – Darunavir/r ↑ ↑ ↑ ↓ Ritonavir ↑↑ ↑↑ ↑↑ ↑ NRTI ABC+3TC ↑ ↑ ↑ – AZT+3TC ↑ ↑ – – TDF+FTC ↓ ↓ ↓ ↑ TDF+3TC ↓ ↓ ↓ – TAF ↑ ↑ ↑ ↑ NNRTI Efavirenz ↑ ↑ ↑ ↑ Nevirapine ↑ – – ↑ Rilpivirine – – – – INSTI Bictegravir – – – – Dolutegravir – – – – Raltegravir – – – – Elvitegravir/c ↑ ↑ ↑ ↑ ↑: Slight increase; ↑↑: Increase; ↓: Decrease; –: No significant effect or unclear; 3TC: Lamivudine; ABC: Abacavir; AZT: Zidovudine; FTC: Emtricitabine; HDL-C: High-density lipoprotein cholesterol; INSTI: Integrase strand transfer inhibitor; LDL-C:Low-density lipoprotein cholesterol; NNRTI: Non-nucleoside reverse transcriptase inhibitor; NRTI: Nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor; TAF: Tenofovir alafenamide; TC: Total cholesterol; TDF: Tenofovir disoproxil fumarate; TG:Triglycerides. Within the current drug framework, preventing the development of metabolic syndrome during treatment remains essential, especially with "lipid-friendly regimens". However, even with such drugs, dyslipidemia cannot be fully explained by pharmacological effects alone, as viral persistence remains closely linked to chronic immune activation through multiple mechanisms, including residual antigen production from viral reservoirs, gut-derived microbial translocation, dysregulation of immune checkpoints, T-cell senescence/exhaustion, and co-infections (Figure 1).[6] Among the HIV viral proteins, Nef has been most extensively studied and is considered a key driver of HIV-associated lipid abnormalities. It impairs cholesterol efflux by inhibiting the ATP-binding cassette transporter A1 (ABCA1) and disrupts lipid raft homeostasis, thereby exacerbating both lipid imbalance and immune activation.[7] Continuous viral production from reservoir cells in ART-treated patients remains a key source of immune activation; making these processes fundamental drivers of chronic HIV-associated inflammation.[8] HIV-related immune activation, particularly via monocyte–macrophage axis dysfunction, impairs cholesterol handling and fosters foam cell formation, contributing to atherogenesis. The envelope glycoprotein gp120 and other structural proteins activate monocytes, triggering chronic immune activation.[9] HIV infection induces the upregulation of CD11b/CD38/CD163 on circulating monocytes alongside expanded pro-inflammatory CD14+CD16+ monocytes with enhanced interleukin(IL)-6, tumor necrosis factor-α (TNF-α), and IL-1β expression.[6,10] Furthermore, microbial translocation can activate monocytes and macrophages via toll-like receptor signaling which results in the production of TNF-α, IL-1β, IL-18.[6] Soluble CD163 and soluble CD14 of activated monocytes are strongly associated with dyslipidemia, contribute to vascular inflammation and endothelial dysfunction.[11] Moreover, by releasing pro-inflammatory cytokines that impair HDL-C function and stimulate hepatic very low density lipoprotein (VLDL) production, these monocytes exacerbate dyslipidemia and, upon entering the vasculature, differentiate into macrophages that uptake oxidized LDL-C and form foam cells, thereby directly driving atherogenesis. Monocytes from virologically suppressed HIV-infected individuals exhibit a pro-atherogenic phenotype, being more prone to foam cell formation under the influence of plasma factors, and characterized by impaired reverse transmigration, defective cholesterol efflux, and downregulated ABCA1 expression.[12]Figure 1: Lipid metabolism dysregulation in people with HIV (PWH). HIV viral persistence leads to chronic immune activation and inflammation, contributing to lipid imbalance. Key factors include T-cell exhaustion, dysfunction of HIV-related monocyte–macrophage axis, and gut microbial translocation. Additionally, ART drugs, especially protease inhibitors, directly alter lipid metabolism and further exacerbate dyslipidemia. These factors collectively accelerate cardiovascular disease progression in PWH (The figure was created with BioRender.com). ART: Antiretroviral therapy; HIV: Human immunodeficiency virus; IL: Interleukin; TNF-α: Tumor necrosis factor-α.In PWH, elevated plasma inflammatory biomarkers, particularly IL-6, D-dimer, and high-sensitivity C-reactive protein (hs-CRP) are significantly associated with increased CVD risk.[13] These findings raise a critical question: should PWH rely primarily on traditional cardiovascular risk control strategies, such as statin use and lifestyle modification, or seek adjunctive immunomodulatory therapies? The REPRIEVE study has shown a definite effect of pitavastatin in reducing major adverse cardiovascular events (MACE) as a primary prevention strategy in PWH.[14] Given the pivotal role of chronic inflammation in dyslipidemia and related CVD, recent research has focused on evaluating anti-inflammatory strategies, marking a paradigm shift from a "lipid-centric" approach toward a dual-path strategy integrating lipid control and inflammation inhibition. Colchicine, a traditional anti-inflammatory drug, significantly reduces the incidence of MACE in CVD patients after percutaneous coronary intervention by suppressing inflammatory mediators,[15] an effect likely mediated through the suppression of short-term postoperative inflammation. Notably, a clinical trial in PWH demonstrated excellent tolerability of colchicine but failed to show benefits in improving coronary endothelial dysfunction.[16] Similarly, IL-1β inhibitors demonstrate MACE prevention potential, with cardioprotective effects unrelated to LDL-C levels.[17] Emerging evidence in PWH demonstrates that IL-1β inhibition with canakinumab significantly reduces inflammatory markers, including hs-CRP , IL-6 , and sCD163, which suggests that targeting IL-1β may represent a promising strategy to mitigate HIV-associated CVD risk.[18] In a crossover clinical trial among PWH, the IL-6 monoclonal antibody tocilizumab significantly reduced several circulating inflammatory markers, but was associated with increases in LDL-C, HDL-C, and lipoprotein-associated phospholipase A2.[19] The cardiovascular benefits of dual-target strategies in PWH remain uncertain and require further investigation in large, long-term trials. This uncertainty extends to lipid-lowering and anti-inflammatory approaches, particularly the use of statins. While statins are thought to have anti-inflammatory properties, their clinical efficacy in this regard has been limited. Inflammation, governed by multiple interconnected pathways, may not be effectively modulated by targeting a single pathway. Therefore, future research must explore the complex interplay between lipid metabolism and inflammation to develop more effective prevention strategies. Author Contributions Xin Huang and Wei Cao jointly participated in the conception and design of the study, as well as the drafting and critical revision of the manuscript. Both authors reviewed the modification suggestions from the editorial office and engaged in the academic defense, approving the final version of the manuscript for publication. Cao Wei, as the corresponding author, was responsible for the overall supervision of the research and academic correspondence. Conflicts of Interest None.